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Review of Herceptin for cancer therapy with focus on

2020-12-29 来源: 51Due教员组 类别: Essay范文

下面为大家整理一篇优秀的essay代写范文 -- Review of Herceptin for cancer therapy with focus on文章描述赫赛汀,又名曲妥珠单抗,在乳腺癌治疗中占有不可替代的地位。它是一种单克隆抗体,参与HER2/neu通路。它主要与HER2/neu受体相互作用以治疗某些乳腺癌。HER2/neu受体也称为酪氨酸蛋白激酶erbB-2。HER2/neu的扩增或过表达会导致癌细胞无限生长。[1]属于人表皮生长因子受体(HER/EGFR/ERBB)家族。近年来,该蛋白作为一种重要的生物标志物被研究,其靶点约占乳腺癌患者的30%。

Pharmacokinetics/pharmacodynamics, and metabolism

Background

 

Herceptin, has another name for trastuzumab, stands the irreplaceable position in breast cancer treatment. It is a kind of monoclonal antibody and involved in HER2/neu pathway. It mainly interacts with HER2/neu receptors to treat certain breast cancer. The HER2/neu receptor is also called tyrosine-protein kinase erbB-2. The Amplification or over-expressed HER2/neu would cause cancer cells to growth unlimited.[1] It belongs to human epidermal growth factor receptor (HER/EGFR/ERBB) family. Recent years, the protein was investigated as an important biomarker which target for approximately 30% of breast cancer patients.[2]

 

Trastuzumab, is a recombinant DNA-derived humanized monoclonal antibody, which is cultured in a sterile medium mammalian cells. The study by Hudis, CA showed that when use trastuzumab to treat late-stage (metastatic) breast cancer patients. The total survival time extent to 20.3 to 25.1 months.[1] Another study selected the early stage breast cancer patient and the results showed that trastuzumab can reduce the risk rate of cancer reviving after surgery to the average 9.5%. Morever, it can aslso reduce the risk of death to 3%. While in this study the side effect is prominent for increased heart problems by 2.1% and the side effect could be able to resolve if trastuzumab is stopped to treat.[3]

 

The trastuzumab, as a drug, was initially discovered by scientists including Dr. Axel Ullrich and Dr. H. Michael Shepard, which was conducted in UCLA's Jonsson Comprehensive Cancer Center. [4] The trade drug, herceptin, was firstly gained approval by FDA in September 1998, which was developed by the biotech company Genentech. Subsequently Dr. Dennis Slamon worked on trastuzumab's development.

 

Pharmacrutical Particulars

List of excipientsL-histidine hydrochloride

L-histidine

α,α-trehalose dihydrate

polysorbate 20

 

Pharmacodynamic properties

 

The pharmacotherapeutic group formation stands the position to ‘Antineoplastic agents’, ‘monoclonal antibodies’, The figure 1 shows the ‘Herceptin 150 mg Powder for concentrate for solution for infusion’, which is produced by Roche and the ATC code is L01XC03. Roche ranks197 in the 500 world rankings, followed by Johnson & Johnson, Pfizer and Novartis. In other words, it ranks fourth among these pharmaceutical companies.

 

As we all known, trastuzumab is a recombinant humanised IgG1 monoclonal antibody. It interacts against the human epidermal growth factor receptor 2 (HER2). There is some studies of examining the HER2-positivity rates in gastric cancer (GC). The methods are using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) or chromogenic in situ hybridization (CISH). The results have shown that HER2 expression broadly vary from 6.8 % to 34.0 % for IHC and 7.1 % to 42.6 % for FISH.[5] In these studies, they compared breast cancer patients whose tumours overexpress HER2 with patients whose tumours do not overexpress HER2. And the results showed that the former one have a shortened disease-free survival compared to the latter patients.

 

Mechanism of action

 

The domain that gtrastuzumab binds with high affinity and specificity is a juxta-membrane region of HER2's extracellular domain. The strong binding of trastuzumab to HER2 influences the HER2 signalling pathways and cuts the proteolytic cleavage in the site of extracellular domain. The results showed that trastuzumab has the function of inhibiting the proliferation of human tumour cells with HER2 over-expression, in both in vitro assays and in animals.[6] Moreover, trastuzumab plays a role as a mediator of antibody-dependent cell-mediated cytotoxicity (ADCC). In vitro study shows that trastuzumab induce the ADCC function to increase HER2 over-expressing cancer cells proliferation compared with cancer cells that do not over-express HER2.

 

However, due to the close relationship between trastuzumab and HER2 expression levels, it is reasonable that Herceptin has the limitation to only be used in patients whose tumours have HER2 overexpression or HER2 gene amplification. We can use  an accurate and validated assay to determine it.[7] Another notable method is to detecte HER2 overexpression by an immuno-histo-chemistry (IHC)-based assessment to examine the fixed tumour samples. [8] HER2 gene amplification should be detected using fluorescence in situ hybridisation (FISH) or chromogenic in situ hybridisation (CISH) of fixed tumour blocks.

 

Pharmacokinetics of trastuzumab

 

The pharmacokinetics of trastuzumab have been studied in patients with some kind of cancer types, including early breast cancer patients ,advanced gastric cancer patients and metastatic breast cancer patients.

 

The drug is mainly injected by intravenous infusions. 10, 50, 100, 250, and 500 mg trastuzumab was injected for short duration intravenous infusions once weekly in patients. The results showed that non-linear pharmacokinetics where clearance decreased with the drug dose increased.The elimination half-life is about 28-38 days. Subsequently the washout period could extent to 27 weeks, that is 190 days or 5 elimination half-lives.

 

Approximately, 25 weeks is the steady state time. A study use the population pharmacokinetic model-dependent assessment of Phase I, II and III clinical trials with two compartment in metastatic breast cancer. AUC predicted the median at steady state over a 21 days period was 1677 mg•day/l. It includes 3 weekly doses of 2 mg/kg Another one is 1793 mg day/l. It includes one every three week dose of 6 mg/kg. [9] The estimated peak of median concentrations were 104 mg/l and 189 mg/l. Moreover, the trough concentrations were 64.9 mg/l and 47.3 mg/l, respectively. One study used the strategy for patients with early breast cancer, who were administered trastuzumab at a loading dose of 8 mg/kg and then followed every three weeks by 6 mg/kg. After that, they use model-independent or non-compartmental analyses (NCA) to analyse the data. The results show the mean steady state trough concentration measured at week 37(cycle 13 ) was 63 mg/l, which was comparable to that reported previously in patients with metastatic breast cancer receiving the weekly regimen.

 

Clearance (CL) for the typical trastuzumab is 0.241 l/day if it is mesured for a body weight of 68 kg.[10] Some studies had evaluated the effects of patient characteristics when they injected trastuzumab.The data showed no change for any of these groups of patients.

 

When examining the overall clinical studies, we can find that the volume of the peripheral compartment and distribution of the central was 3.02 l and 2.68 l, respectively.

 

For advanced gastric cancer, a study use a two compartment nonlinear population pharmacokinetic model. It is a Phase III study BO18255 and was conducted to estimate the steady state pharmacokinetics in patients who administered trastuzumab at a loading dose of 8 mg/kg and then followed by a every three weeks dose of 6 mg/kg. [11] Because the serum levels of trastuzumab were lower than breast cancer patients receiving the same dosing regimen, total clearance was suggested to be much higher for AGC patients. It is hard to say the reason based on present knowledge about the drug. When using trastuzumab at high concentrations, total clearance is dominated by linear clearance, and the half-life in AGC patients is maximize 26 days. The median predicted steady-state AUC values is 1213 mg•day/L, which is over 21days at steady state. [12] However, the median steady-state max concentration is equal to 132 mg/l and the median steady-state mini concentration values is 27.6 mg/L.

 

Preclinical safety data

 

There was no evidence of acute or multiple dose-related toxicity in studies of recently. It is the same as for reproductive toxicity in teratology, female fertility or late gestational toxicity/placental transfer studies. Their results showed that herceptin is not genotoxic. [13] A study of trehalose showed that a major formulation excipient did not reveal any toxicities.

 

A recent study conduct the 4-week intrathecal toxicity and pharmacokinetic study with trastuzumab in cynomolgus monkeys. There are two barriers namey the blood-brain barrier and blood-cerebrospinal fluid (CSF) barrier may prevent trastuzumab from reaching appropriate concentrations in the brain. To evaluate the potential of effects on the central nervous system, a 4-week toxicology study with weekly intrathecal administration of trastuzumab was performed in cynomolgus monkeys at doses of 0, 3, or 15 mg. No trastuzumab-related effects on body weight, clinical signs, neurological function, clinical pathology, or anatomic pathology were noted. The applied doses and CSF concentrations achieved  exceeded those reported in patients.For patients with brain metastases in HER2-positive breast cancer, the results support future studies for further evaluation of intrathecal application of trastuzumab.[14]

 

In clinical trials, if the patients with MBC who have tumours that overexpress HER2 and even have failed one or more chemotherapy regimens, they can still try  herceptin has been used as monotherapy for their metastatic disease. Moreover, herceptin has also been used in combination with paclitaxel or docetaxel in order to treat patients who were blank for chemotherapy for their metastatic disease. While patients who had already been conducted anthracycline-based adjuvant chemotherapy were treated with paclitaxel with or without Herceptin. For example, in one of the clinical trial of docetaxel with or without Herceptin, around 60 % of the patients had already have prior anthracycline-based adjuvant chemotherapy. [15]

 

Method of administration

 

Herceptin treatment need only be initiated by a doctor who was experienced in the administration of cytotoxic chemotherapy. In other words, patients should be administered by a healthcare professional only. It is important to double check the product labels to ensure that the correct formulation, including intravenous or subcutaneous fixed dose, will be administered to the patient. Herceptin intravenous formulation has no difference for subcutaneous administration. So you can only administer the drug via an intravenous infusion .

 

What is more important, checking the vial labels is needed in order to prevent medication errors so that to ensure that the drug being prepared and administered is Herceptin (trastuzumab) and not trastuzumab emtansine.

 

Bioavailability

 

For metastatic breast cancer, there is three-weekly schedule for the treatment.

We recommended initial loading dose for 8 mg/kg of the body weight. And the recommended maintenance dose at three-weekly intervals is 6 mg/kg body weight, beginning three weeks after the loading dose.[16] If the drug was injected Weekly. The schedule is for recommendation initial loading dose of Herceptin is 4 mg/kg body weight. The recommended weekly maintenance dose of Herceptin is 2 mg/kg body weight, injecting one week after the loading dose.[17]

 

The effects when it is administered in combination with paclitaxel or docetaxel. In the pre-clinical trials, paclitaxel or docetaxel was administered separately the day after the first dose of Herceptin. Another strategy is immediately injection after the subsequent doses of Herceptin in the condition of the preceding dose of Herceptin was well tolerated.[18]

 

Aromatase inhibitor is another effective drug that could be administered in combination with Herceptin. The pre-clinical trial conduct the experiments by administer both Herceptin and anastrozole from day 1. [19] Compared with the above two drug, there were no other restrictions on the relative timing of Herceptin and anastrozole at administration.

 

In clinical trials, there is no need to reduce the dose of Herceptin. Patients may continue therapy during periods of reversible, chemotherapy-induced myelo-suppression. However, they should be monitored carefully for complications of neutropenia during these period. There is some dedicated pharmacokinetic studies which investigate the older people with renal or hepatic impairment have been carried out. In a population pharmacokinetic analysis, age and renal impairment have no influence to affect trastuzumab disposition.[20]

 

Other warnings should take enough attation for treatment. For example, a health-care provider should be prepared well for anaphylaxis and an emergency kit when use herceptin intravenous infusion. [21] Moreover, real-time observation should be processed that the patients should be observed for at least six hours after the first infusion. Then they also to be under observation every two hours after the subsequent infusions for symptoms like fever and chills or other infusion-related symptoms. Once the unusual symptoms occurred, interruption or slowing the rate of the infusion may help control it. When these kind of symptoms abate, the infusion may be resumed.

 

Conclusion

Herceptin, as one of the most effective anti-cancer drug, had been in the drug history for a long time. Its function and pharmacokinetics have been researched by a lot of researchers both in vivo and in vrito or animal and human clinical test. So, it is trustworthy to believe the effect of such an drug. Combination with other drug would be promising in the future and modification of the drug is also in the process of drug development history. Roche would still stands the irreplaceable place for the production of this drug.

Figure

 

Figure 1. Herceptin 150 mg Powder for concentrate for solution for infusion

 

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